Identification of the Promoter of Human Carbonyl Reductase 3 (CBR3) and Impact of Common Promoter Polymorphisms on Hepatic CBR3 mRNA Expression

Abstract

Recent studies suggest that polymorphisms in human carbonyl reductase 3 (CBR3) influence the pharmacodynamics of doxorubicin. First, we sought to identify the promoter of CBR3. Next, we examined whether two CBR3 promoter polymorphisms (CBR3 -725T>C and CBR3 -326T>A) dictate promoter activity and hepatic CBR3 mRNA levels. The promoter activities of CBR3 reporter constructs were investigated in HepG2 and MCF-7 cells. CBR3 mRNA levels were documented in 95 liver samples from white (n = 62) and black (n = 33) donors. Genotype-phenotype correlation analyses were used to determine the impact of the CBR3 -725T>C and CBR3 -326T>A polymorphisms on hepatic CBR3 mRNA levels. We identified the promoter of human CBR3. Liver samples from black donors showed higher relative CBR3 mRNA levels than samples from whites (CBR3 mRNA(blacks) = 3.0 +/- 3.1 relative fold vs. CBR3 mRNA(whites) = 1.6 +/- 1.5 relative fold, p = 0.021). The variant -725C and -326A alleles did not modify the gene reporter activities of engineered CBR3 promoter constructs. In line, hepatic CBR3 mRNA levels were not associated with CBR3 -725T>C and CBR3 -326T>A genotype status. These studies provide the first insights into the regulation and variable hepatic expression of polymorphic CBR3.